Liver cell-based systems are widely used to study drug metabolism, toxicity and liver disease. However, the poor correlation between in vitro data and clinical outcomes is very real, and attributed in part to the missing physiological context of the hepatic microenvironment (sinusoidal flow and transport, three dimensional architecture and heterotypic cell-cell interactions). HemoShear, LLC is a biotechnology research company that utilizes patented methodologies (US 7,811,782) to restore in vivo biology to animal and human primary cells in co-culture in vitro. Recently, under the SBIR mechanism, HemoShear has commercialized in vitro rat and human primary hepatocyte systems that combine physiological principles of hemodynamics and transport to restore and maintain in vivo-like differentiated hepatocyte phenotype and function. Primary hepatocytes in this system respond to drugs and risk factors at concentrations that approximate in vivo and clinical response levels, a major advantage for our commercial partners (see Letters of Support). However, in spite of the rapid commercial uptake of this single cell type system (primary hepatocytes only), this platform could fail to capture drug toxicities requiring the involvement of multiple liver cell types, e.g. non-parenchymal cells (NPCs), resulting in preclinical false-negatives that manifest toxicity in the clinic. The purpose of this Fast-Track SBIR is to develop a human physiological hepatocyte:NPC multi-cellular liver system and validate drugs that are known to cause drug-induced liver injury through an NPC-mediated process, for which there are currently no such preclinical human-based systems.